Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesized insulin receptors to the cell surface.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and activates a signaling network known as the unfolded protein response (UPR). Here we characterize how ER stress and the UPR inhibit insulin signaling. We find that ER stress inhibits insulin signaling by depleting the cell surface population of the insulin receptor.

A chemical potentiator of copper-accumulation used to investigate the iron-regulons of Saccharomyces cerevisiae.

The extreme resistance of Saccharomyces cerevisiae to copper is overcome by 2-(6-benzyl-2-pyridyl)quinazoline (BPQ), providing a chemical-biology tool which has been exploited in two lines of discovery. First, BPQ is shown to form a red (BPQ)2 Cu(I) complex and promote Ctr1-independent copper-accumulation in whole cells and in mitochondria isolated from treated cells. Multiple phenotypes, including loss of aconitase activity, are consistent with copper-BPQ mediated damage to mitochondrial iron-sulphur clusters.

Co(ll)-detection does not follow Kco(ll) gradient: channelling in Co(ll)-sensing.

The MerR-like transcriptional activator CoaR detects surplus Co(ll) to regulate Co(ll) efflux in a cyanobacterium. This organism also has cytosolic metal-sensors from three further families represented by Zn(ll)-sensors ZiaR and Zur plus Ni(ll)-sensor InrS. Here we discover by competition with Fura-2 that CoaR has KCo(ll) weaker than 7 × 10(-8) M, which is weaker than ZiaR, Zur and InrS (KCo(ll) = 6.

Cyanobacterial metallochaperone inhibits deleterious side reactions of copper.

Copper metallochaperones supply copper to cupro-proteins through copper-mediated protein-protein-interactions and it has been hypothesized that metallochaperones thereby inhibit copper from causing damage en route. Evidence is presented in support of this latter role for cyanobacterial metallochaperone, Atx1. In cyanobacteria Atx1 contributes towards the supply of copper to plastocyanin inside thylakoids but it is shown here that in copper-replete medium, copper can reach plastocyanin without Atx1.

Structure and metal loading of a soluble periplasm cuproprotein.

A copper-trafficking pathway was found to enable Cu(2+) occupancy of a soluble periplasm protein, CucA, even when competing Zn(2+) is abundant in the periplasm. Here, we solved the structure of CucA (a new cupin) and found that binding of Cu(2+), but not Zn(2+), quenches the fluorescence of Trp(165), which is adjacent to the metal site. Using this fluorescence probe, we established that CucA becomes partly occupied by Zn(2+) following exposure to equimolar Zn(2+) and Cu(2+).

Interaction between cyanobacterial copper chaperone Atx1 and zinc homeostasis.

Cyanobacterial Atx1 is a copper chaperone which interacts with two copper-transporting ATPases to assist copper supply to plastocyanin and cytochrome oxidase. ZiaA is a Zn(2+)-exporting ATPase and ziaA expression is regulated by ZiaR. Here we show that gene expression from the ziaA operator promoter, monitored using reverse transcriptase PCR and lacZ fusions, is elevated in Deltaatx1 mutants.

Response of Schizosaccharomyces pombe to zinc deficiency.

A component of the cellular response to zinc deficiency operates via control of transcript abundance. Therefore, microarray analysis was employed to identify Schizosaccharomyces pombe genes whose mRNA levels are regulated by intracellular zinc status. A set of 57 genes whose mRNA levels were substantially reduced in response to zinc deficiency was identified, while the mRNA levels of 63 genes were increased by this condition.